Hepatitis B virus (HBV) is one of several viruses known to cause liver disease (e.g., chronic active hepatitis, cirrhosis, liver failure and hepatocellular carcinoma) in humans. HBV is spread through percutaneous or mucosal contact with infected body fluids. According to the World Health Organization (WHO), nearly two billion people are infected with HBV, which causes over 600,000 fatalities each year (WHO, Fact Sheet No. 204, 2009).
The HBV virion is composed of a core antigen (HBcAg), which encapsulates viral DNA, and a surface antigen (HBsAg), which is located on the viral outer membrane. HBsAg, previously known as the Australian antigen, is composed of three glycoproteins having a shared carboxy terminal sequence: S (S only); M (pre-S2 and S); and L (pre-S1, pre-S2 and S). HBsAg self-associates to form 22 nm particles that are released from infected hepatocytes.
All HBV vaccines approved for use in humans are based on noninfectious HBsAg particles. In the United States, the current HBV vaccines are recombinant subunit vaccines produced in yeast (e.g., RECOMBIVAX HB® hepatitis B vaccine marketed by Merck & Co.; and ENGERIX-B® hepatitis B vaccine marketed by GlaxoSmithKline). These HBV vaccines are formulated as HBsAg adsorbed to alum.
Use of the current vaccines is hindered by the typical lengthy administration regimen (e.g., generally three or four doses over six to twelve months). In addition, only 10-20% of adult vaccine recipients mount a seroprotective immune response within one month of receiving a first dose of a HBV vaccine (Andre and Sarary, Post Grad Med J, 63: 169-178, 1987; and Keating and Noble, Drugs 2003, 63:1021-1051, 2003). This delay in the generation of a protective antibody response is of particular importance for individuals at high risk of HBV infection (e.g., health care workers, emergency first responders, or individuals in high-risk behavior groups). Further, compliance in returning for three or four injections over six to twelve months can be poor.
Another serious shortcoming of the current HBV vaccines is the high level of hypo- or non-responders (30-60% hypo- or nonresponders after the recommended regimen) among some groups, such as those over 40 years of age (Denis et al., J Infect Dis, 149:1019, 1984; Averoff et al., Am J Prev Med, 15:1-8, 1998; and Treadwell et al., Am J Med, 95:584-588, 1993), and subjects with renal failure or diabetes (Weber et al., JAMA, 254:3187-3189, 1985). Thus, development of a more potent HBV vaccine with more rapid induction of protective immunity, and improved response among hypo-responder populations is of major importance in reducing HBV infection.